Heterocyclic aromatic oxazole compounds and use thereof

ABSTRACT

A heterocyclic aromatic oxazole compound of the formula (I)  
                 
 
     wherein Z is an oxygen atom; one of R and R 1  is a group of the formula  
                 
 
     wherein R 3  is lower alkyl, amino or lower alkylamino, and R 4 , R 5 , R 6  and R 7  are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R 4 , R 5 , R 6  and R 7  is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R 2  is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof. The heterocyclic aromatic oxazole compound and pharmaceutically acceptable salts thereof have antipyretic action, analgesic action, anti-inflammatory action, and particularly, selective inhibitory action on cyclooxygenase-2 (COX-2), and are expected to be useful as anti-inflammatory agents with less side-effects such as digestive tract disorders.

TECHNICAL FIELD

[0001] The present invention relates to novel heterocyclic aromaticoxazole compounds. More particularly, the present invention relates toheterocyclic aromatic oxazole compounds having antipyretic activity,analgesic activity, anti-inflammatory activity, and in particular,selective inhibitory activity against cyclooxygenase-2 (COX-2),pharmaceutically acceptable salts thereof, intermediates for producingthem and pharmaceuticals useful as anti-inflammatory agents causing lessside-effects such as disorders in the digestive tract, which comprisethese heterocyclic aromatic oxazole compounds.

BACKGROUND ART

[0002] It has been conventionally known that arachidonic acidmetabolites, prostaglandin E₂ (PGE₂), prostaglandin I₂ (PGI₂) andthromboxane B₂ (TXB₂) are deeply involved in inflammations. An importantenzyme in this arachidonic acid metabolism is cyclooxygenase.Cyclooxygenase is a synthase which produces prostaglandin H₂ (PGH₂) fromarachidonic acid via prostaglandin G₂ (PGG₂), and includescyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).

[0003] With respect to COX-1, cDNA cloning was performed in 1988 and itsprimary structure and induction by various factors have been clarified[Yokoyama, C. et al.: Biochem. Biophys. Res. Commun., 165:888-894(1989); Smith, W. L. et al.: Biochim. Biophys. Acta, 1083: 1-17 (1991);DeWitt, D. L.: Biochim. Biophys. Acta, 1083:121-134 (1991)]. On theother hand, the existence of an isozyme of COX-1, namely, COX-2, wassuggested in 1989 [Holtzman, M. J. et al.: J. Biol. Chem.,267:21438-21445 (1992)], and cDNAs of COX-2 of chicken, mouse and humanhave been cloned since 1991 [Xie, W. et al.: Proc. Natl. Acad. Sci. USA,88:2692-2696 (1991); Kujubu, D. A. et al.: J. Biol. Chem.,266:12866-12872 (1991); Hla, T. et al.: Proc. Natl. Acad. Sci. USA,89:7384-7388 (1992)]. COX-2 is quickly induced by phorbol ester,lipopolysaccharide (LPS) and the like, and the relationship withinflammation and bronchial asthma has been inferred.

[0004] COX-1 systemically and constantly exists in almost all cells andis physiologically concerned with the generation of prostaglandin (PG)necessary for the functions of, for example, stomach and kidney.Therefore, when COX-1 is inhibited, the biosynthesis of PG byvasodilative PGE₂ and PGI₂, which protect gastric mucosa, is suppressed,and the protective action on the gastric mucosa becomes degraded, as aresult of which ulcer is caused. With regard to a symptom associatedwith a decrease in renal blood flow, in general terms, the renal bloodflow can be increased by promoting the production of vasodilative PGE₂in the body, thereby to appropriately maintain glomerular filtrationrate. However, if the production of such vasodilative PG is suppresseddue to the inhibition of COX-1, the renal blood flow becomes less, sothat a side-effect such as the onset of ischemic acute renalinsufficiency is sometimes caused.

[0005] On the other hand, COX-2 exists in particular sites such asmonocytes, synovial cells, granulosa cells and intravenous endothelialcells, and is topically expressed when inflammation is caused. It istherefore considered that PG generated by COX-2 is deeply concerned withinflammation and tissue disorders.

[0006] Currently, non-steroidal anti-inflammatory drugs (NSAID) such asaspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen andnaproxen have been widely used in clinical situations. Most of theseNSAIDs are anti-inflammatory drugs which selectively inhibitcyclooxygenase (COX) and are associated with side-effects such asdisorders in the digestive tract. Such side-effects are considered to becaused by the fact that they, though certainly selectively inhibit COX,inhibit both COX-1 and COX-2.

[0007] It follows therefrom that selective inhibition, withoutinhibition of COX-1, of solely COX-2 which is specifically induced atthe inflammatory sites, would enable provision of a superioranti-inflammatory drug free of side-effects such as disorders in thedigestive tract (e.g., ulcer).

[0008] There are various reports on anti-inflammatory drugs havingselective COX-2 inhibitory activity, which aim at reducing side-effectssuch as disorders in the digestive tract.

[0009] For example, WO94/15932 discloses, as COX-2 inhibitors,5-membered heterocyclic compounds substituted by bisaryl, such asthiophene, furan and pyrrole, which are specifically exemplified by3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene. However, thispublication merely shows a 5-membered heterocyclic compound such asthiophene having aryl or heteroaryl at the 3-position or 4-position.

[0010] Moreover, various reports deal with anti-inflammatory drugshaving cyclooxygenase-inhibitory action, prostaglandinsynthesis-inhibitory action or thromboxane A₂ synthesis-inhibitoryaction.

[0011] For example, Japanese Patent Unexamined Publication No.141261/1991 discloses pyrazole derivatives such as ethyl1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate;Japanese Patent Unexamined Publication No. 183767/1982 disclosesthiazole derivatives such as2-methylthio-5-phenyl-4-(3-pyridyl)-thiazole; and Japanese PatentUnexamined Publication No. 58981/1985 discloses thiazole derivativessuch as 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. Thesepublications mention that they are useful as anti-inflammatory drugs,whereas they do not disclose if they have selective inhibitory action onCOX-2 to reduce side-effects, or any suggestion of it.

[0012] There are other reports on the following heterocyclic aromaticcompounds.

[0013] For example, U.S. Pat. No. 4,632,930 discloses oxazole compoundssuch as5-cyclohexyl-4-(4-mthylsulfonylphenyl)-α,α-bis(trifluoromethyl)oxazole-2-methanol.Yet, the compounds disclosed therein are effective for hypertension andtheir usefulness as anti-inflammatory drugs or any suggestion to thateffect are not included.

[0014] Japanese Patent Application under PCT laid-open under Kohyo No.500054/1984 discloses oxazole derivatives having heteroaryl or carbonring aryl at the 4-position or 5-position of oxazole ring and havingcarboxy, ester or amidized carboxy via lower alkylene at the 2-positionthereof, such as ethyl2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese PatentApplication under PCT laid-open under Kohyo No. 500055/1984 disclosesimidazole derivatives having heteroaryl and/or carbon ring aryl at the4-position or 5-position of imidazole ring and having formyl oracetalized formyl via lower alkylene at the 2-position thereof, such as2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl acetal.These publications teach that these compounds are effective as dermalantiphlogistic or mucosal antiphlogistic for inflammatory dermaldiseases, but do not teach or even suggest that they have selectiveinhibitory action on COX-2.

[0015] Japanese Patent Unexamined Publication No. 70446/1993 disclosesN-thiazolylsulfonamide derivatives such asN-[5-cyclohexyl-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide;and Japanese Patent Unexamined Publication No. 83372/1990 disclosescyclohexylimidazole derivatives such as4-cyclohexyl-5-phenyl-2-t-butyl-imidazole. These publications onlyexemplify cyclohexyl as a substituent and include no suggestion as tothe substitution with phenyl substituted by aminosulfonyl, loweralkylaminosulfonyl or lower alkylsulfonyl.

[0016] WO94/27980 discloses oxazole compounds such as2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2inhibitors. However, the compounds described in this publication aremainly characterized by 4-fluorophenyl and 4-methylsulfonylphenyl at the4-position and 5-position of oxazole ring, and do not suggest thecompounds having specific substituents in combination, as in the presentinvention.

[0017] Not only in COX-2 inhibitors but also in the field ofanti-inflammatory drugs, preferable phenyl substituent for 5-memberedheterocyclic ring skeleton has been conventionally considered to bemonosubstituted phenyl such as 4-methylsulfonylphenyl and4-methoxyphenyl, and di-substituted phenyl has been barely tried (e.g.,UK Patent No. 1206403).

DISCLOSURE OF THE INVENTION

[0018] The present inventors have intensively studied with the aim ofproviding a novel compound having antipyretic activity, analgesicactivity and anti-inflammatory activity, which is free of side-effectssuch as disorders in the digestive tract. Surprisingly, they have foundthat a compound having a secondary substituent such as halogen atom, inparticular, fluorine atom, introduced into phenyl such as 4-loweralkylsulfonylphenyl, 4-aminosulfonylphenyl or 4-loweralkylaminosulfonylphenyl, as a substituent for oxazole, has superiorselective inhibitory action on COX-2, which resulted in the completionof the present invention.

[0019] That is, the present invention relates to heterocyclic aromaticoxazole compounds as shown in the following (1) to (21),pharmaceutically acceptable salts thereof, intermediate compounds forproducing such compounds and pharmaceutical compositions comprising suchheterocyclic aromatic oxazole compound.

[0020] (1) Heterocyclic aromatic oxazole compounds of the formula (I)

[0021]  wherein

[0022] Z is an oxygen atom;

[0023] one of R and R₁ is a group of the formula

[0024]  wherein

[0025] R₃ is lower alkyl, amino or lower alkylamino, and

[0026] R₄, R₅, R₆ and R₇ are the same or different and each is hydrogenatom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyor amino, provided that at least one of R₄, R₅, R₆ and R₇ is nothydrogen atom, and the other is optionally substituted cycloalkyl,optionally substituted heterocyclic group or optionally substitutedaryl; and

[0027] R₂ is a lower alkyl or a halogenated lower alkyl, and

[0028]  pharmaceutically acceptable salts thereof.

[0029] (2) Heterocyclic aromatic oxazole compounds of the above (1),wherein R₁ is a group of the formula

[0030] wherein R₃′ is lower alkyl or amino, at least one of R₄′, R₅′,R₆′ and R₇′ is halogen atom or lower alkyl and the rest is hydrogen atomor halogen atom, and pharmaceutically acceptable salts thereof.

[0031] (3) Heterocyclic aromatic oxazole compounds of the above (1),wherein R₁ is a group of the formula

[0032] wherein R₃″ is methyl or amino, R₅″ is fluorine atom and R6″ ishydrogen atom or fluorine atom, and R₂ is methyl, and pharmaceuticallyacceptable salts thereof.

[0033] (4) Heterocyclic aromatic oxazole compounds of the above (1),wherein R₁ is a group of the formula

[0034] wherein R₃″ , R₅″ and R₆″ are as defined in the above (3); R isoptionally substituted cycloalkyl having 5 to 7 carbon atoms, optionallysubstituted thienyl, optionally substituted furyl, optionallysubstituted pyrrolyl, optionally substituted morpholino, optionallysubstituted piperazinyl, optionally substituted piperidyl, optionallysubstituted phenyl, optionally substituted naphthyl or optionallysubstituted biphenyl, and R₂ is methyl, and pharmaceutically acceptablesalts thereof.

[0035] (5) Heterocyclic aromatic oxazole compounds of the above (4),wherein R₃″ is amino, and pharmaceutically acceptable salts thereof.

[0036] (6) Heterocyclic aromatic oxazole compounds of the above (4),wherein R is optionally substituted cycloalkyl having 5 to 7 carbonatoms, optionally substituted phenyl or optionally substituted thienyl,and pharmaceutically acceptable salts thereof.

[0037] (7) Heterocyclic aromatic oxazole compounds of the above (4),wherein R is cyclohexyl or 4-fluorophenyl, and R₁ is4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl,3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl,and pharmaceutically acceptable salts thereof.

[0038] (8) Heterocyclic aromatic oxazole compounds of the above (1),which are selected from the group of:

[0039] 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,

[0040] 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole,

[0041]5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole,

[0042]4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazole,and

[0043]5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole,

[0044]  and pharmaceutically acceptable salts thereof.

[0045] (9) Oxime compounds of the following formula (XI′)

[0046] wherein R₁″ is

[0047] wherein R₄, R_(5,) R₆ and R₇ are as defined in the above (1), andR″ is optionally substituted cycloalkyl or optionally substituted aryl.

[0048] (10) Oxime compounds of the above (9) wherein R₁″ is3-fluorophenyl or 3,5-difluorophenyl, and R″ is cyclohexyl or4-fluorophenyl.

[0049] (11) Ketone compounds of the following formula (IV″)

[0050] wherein R₁″ and R″ are respectively as defined in the above (9).

[0051] (12) Ketone compounds of the above (11) wherein R₁″ is3-fluorophenyl or 3,5-difluorophenyl, and R₁″ is cyclohexyl or4-fluorophenyl.

[0052] (13) Ketomethylene compounds of the following formula (IV′″)

[0053] wherein R′″ is optionally substituted cycloalkyl having 5 to 7carbon atoms, optionally substituted phenyl or optionally substitutedthienyl, and R₁′″ is a group of the formula

[0054] wherein R₃′, R₄′, R₅′, R₆′ and R₇′ are as defined in the above(2).

[0055] (14) Ketomethylene compounds of the above (13) wherein R′″ iscyclohexyl, and R₁′″ is 4-aminosulfonyl-3-fluorophenyl,4-amino-sulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or3,5-difluoro-4-methylsulfonylphenyl.

[0056] (15) Ester compounds of the following formula (V)

[0057] wherein R, R₁, R₂ and Z are as defined in the above (1).

[0058] (16) Ester compounds of the above (15) wherein R is cycloalkyland R₂ is lower alkyl.

[0059] (17) Amide compounds of the following formula (XVIII′)

[0060] wherein R₁″ and R″ are respectively as defined in the above (9),and Z and R₂ are as defined in the above (1).

[0061] (18) Amide compounds of the above (17) wherein R₁″ is3-fluorophenyl or 3,5-difluorophenyl, R″ is cyclohexyl or4-fluorophenyl, and R₂ is lower alkyl.

[0062] (19) Pharmaceutical compositions comprising a pharmaceuticallyacceptable carrier, and a heterocyclic aromatic oxazole compound of theabove (1) or a pharmaceutically acceptable salt thereof.

[0063] (20) Cyclooxygenase-2 inhibitors comprising a pharmaceuticallyacceptable carrier, and a heterocyclic aromatic oxazole compound of theabove (1) or a pharmaceutically acceptable salt thereof as an activeingredient.

[0064] (21) Anti-inflammatory agents comprising a pharmaceuticallyacceptable carrier, and a heterocyclic aromatic oxazole compound of theabove (1) or a pharmaceutically acceptable salt thereof as an activeingredient.

[0065] As used herein, lower alkyl means an optionally branched alkylhaving 1 to 4 carbon atoms, which is exemplified by methyl, ethyl,propyl, isopropyl, butyl,. isobutyl, sec-butyl and tert-butyl, withpreference given to methyl.

[0066] Lower alkylamino is that wherein amino group is substituted bythe above-mentioned lower alkyl, and is exemplified by methylamino,dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino,butylamino, isobutylamino, sec-butylamino and tert-butylamino. Preferredare methylamino and dimethylamino.

[0067] Halogen atom means chlorine atom, bromine atom, fluorine atom andthe like, with preference given to chlorine atom and fluorine atom.Particularly preferred is fluorine atom.

[0068] Lower alkoxy is an optionally branched alkoxy having 1 to 4carbon atoms, which is exemplified by methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, withpreference given to methoxy.

[0069] Cycloalkyl means a cycloalkyl having 3 to 8 carbon atoms, whichis exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, with preference given to cycloalkyl having 5to 7 carbon atoms, such as cyclopentyl, cyclohexyl and cycloheptyl.Particularly preferred is cyclohexyl.

[0070] Heterocyclic group is a 5- or 6-membered aromatic heterocyclicring, saturated heterocyclic ring or condensed heterocyclic ring ofthese heterocyclic rings and benzene ring, all having, besides carbonatom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom as atom(s) constituting the ring. Examples thereof includethienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, morpholino, piperazinyl, piperidyl,pyranyl, thiopyranyl, pyridyl, benzothienyl, benzofuranyl, indole,4,5,6,7-tetrahydroindole, 4,5,6,7-tetrahydrobenzothienyl and4,5,6,7-tetrahydrobenzofuranyl, with preference given to thienyl, furyl,pyrrolyl, morpholino, piperazinyl and piperidyl, and particularpreference given to thienyl.

[0071] Aryl is, for example, phenyl, naphthyl or biphenyl. Preferred isphenyl.

[0072] Halogenated lower alkyl is that wherein lower alkyl issubstituted by the above-mentioned halogen atom, and is exemplified byfluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl,dichloromethyl, trifluoromethyl, trichloromethyl, fluoroethyl,chloroethyl, difluoroethyl, dichloroethyl, trifluoroethyl,trichloroethyl, tetrachloroethyl, pentafluoroethyl and fluoropropoyl,with preference given to fluoromethyl, chloromethyl, dichloromethyl,difluoromethyl, trichloromethyl and trifluoromethyl.

[0073] “Optionally substituted” means that the group may be substitutedby 1 to 3 substituents wherein said substituents may be the same ordifferent. The position of the substituents is optional and is notparticularly limited. Specific examples include lower alkyl such asmethyl, ethyl, propyl, isopropyl, butyl and tert-butyl; hydroxy; loweralkoxy such as methoxy, ethoxy, propoxy and butoxy; halogen atom such asfluorine, chlorine and bromine; nitro; cyano; acyl such as formyl,acetyl and propionyl; acyloxy such as formyloxy, acetyloxy andpropionyloxy; mercapto; alkylthio such as methylthio, ethylthio,propylthio, butylthio and isobutylthio; amino; alkylamino such asmethylamino, ethylamino, propylamino and butylamino; dialkylamino suchas dimethylamino, diethylamino, dipropylamino and dibutylamino;carbonyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl; amide; trifluoromethyl; alkylsulfonyl such asmethylsulfonyl and ethanesulfonyl; aminosulfonyl; cycloalkyl such ascyclopentyl and cyclohexyl; phenyl; and acylamide such as acetamide andpropionylamide. Preferred are hydroxy, lower alkyl, lower alkoxy,mercapto, lower alkylthio, halogen atom, trifluoromethyl, alkylcarbonyl,alkoxycarbonyl and acylamide.

[0074] More specifically, optionally substituted aryl means an arylwhich may be substituted-by halogen atom, hydroxy, lower alkyl, loweralkoxy, lower alkylsulfonyl and aminosulfonyl, particularly phenyl, andis exemplified by phenyl, fluorophenyl, methylphenyl, methoxyphenyl,methylsulfonylphenyl and aminosulfonylphenyl, with preference given tophenyl and 4-fluorophenyl.

[0075] Optionally substituted heterocyclic group means a heterocyclicgroup which may be substituted by halogen atom, hydroxy, lower alkyl,lower alkoxy, lower alkylsulfonyl and aminosulfonyl, and particularlymeans thienyl, furyl, 5-methylthienyl and 5-chlorothienyl. Optionallysubstituted cycloalkyl means a cycloalkyl which may be substituted bythe same substituents as above, with preference given to cyclohexyl.

[0076] Examples of preferable R of the heterocyclic aromatic oxazolecompounds of the present invention include cyclohexyl, 4-fluorophenyland 5-chlorothienyl, with particular preference given to cyclohexyl.Preferred as R₁ is a group of the formula

[0077] wherein R₃, R₄, R₅, R₆ and R₇ are as defined above, withparticular preference given to a group wherein R₃ is amino or methyl, R₄and R₇ are hydrogen atoms and at least one of R₅ and R₆ is fluorineatom. Specific examples include 4-aminosulfonyl-3-fluorophenyl,3-fluoro-4-methylsulfonylphenyl, 4-aminosulfonyl-3,5-difluorophenyl and3,5-difluoro-4-methylsulfonylphenyl, with particular preference given to4-aminosulfonyl-3-fluorophenyl. Preferred as R₂ is methyl.

[0078] Pharmaceutically acceptable salt may be any as long as it forms anon-toxic salt with the oxazole derivative of the formula (I). Alkalimetal salts such as sodium salt and potassium salt, alkaline earth metalsalts such as magnesium salt and calcium salt, ammonium salt, organicbase salts such as trimethylamine salt, triethylamine salt, pyridinesalt, picoline salt, dicyclohexylamine salt andN,N′-dibenzylethylenediamine salt, and amino acid salts such as lysinesalt and arginine salt are among the examples. It may be a hydrate asthe case demands.

[0079] The compound of the present invention has particularly superiorselective inhibitory action on COX-2 and is expected to make atherapeutic drug useful for antipyresis, pain relief andanti-inflammation, which is free of side-effects such as digestive tractdisorders.

[0080] When the compound of the formula (I) of the present invention ora pharmaceutically acceptable salt thereof is used as a pharmaceuticalpreparation, it is generally admixed with pharmacologically acceptablecarriers, excipients, diluents, extenders, disintegrators, stabilizers,preservatives, buffers, emulsifying agents, aromatics, colorings,sweeteners, thickeners, flavorings, solubilizers and other additivesknown per se, such as water, vegetable oil, alcohol such as ethanol andbenzyl alcohol, polyethylene glycol, glycerol triacetate gelatin,carbohydrates such as lactose and starch, magnesium stearate, talc,lanolin and petrolatum, and formulated into, by a conventional method,tablets, pills, powders, granules, suppositories, injections, eye drops,liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions,syrups and the like, which can be administered orally or parenterally.

[0081] While the dose varies depending on the kind and severity of thedisease, compound to be administered, administration route, and age,sex, body weight etc. of patients, 0.1 mg-1,000 mg, particularly 1mg-300 mg of compound (I) is generally administered orally to an adultper day.

[0082] The compounds of the present invention can be produced, forexample, by the following methods. It is needless to say that the methodfor producing the compounds of the present invention is not limited tothese methods.

[0083] wherein R₂′ is lower alkyl or halogenated lower alkyl wherein R₂′may be the same with or different from R₂, X and X′ are the same ordifferent and each is halogen atom such as bromine atom and chlorineatom, X₁ is halogen atom or hydroxy, X₁′ is halogen atom or hydroxy oralkali metal derivative thereof, and R, R₁, R₂ and Z are as definedabove.

[0084] Step 1

[0085] Compound (IV) can be synthesized by reacting compound (II) withcompound (III) in the presence of a metal such as zinc and magnesium inan inert solvent such as 1,2-dimethoxyethane, dioxane, ether,tetrahydrofuran, methylene chloride, benzene and toluene at roomtemperature. In this case, a catalyst such as palladium(O) complex andcopper(I) complex may be added.

[0086] Step 2

[0087] Compound (V) can be synthesized by reacting compound (IV) inacetic acid solvent in the presence of lead tetraacetate, or byrefluxing compound (IV) under heating in the presence of a complex suchas manganese acetate, in lower alkanecarboxylic acid such as acetic acidand propionic acid corresponding to R₂COOH wherein R₂ is as definedabove and benzoic acid and a solvent such as benzene as necessary.

[0088] Step 3

[0089] Compound (I) can be synthesized by refluxing compound (V) underheating in the presence of ammonium salt (e.g., lower alkanecarboxylicacid ammonium such as ammonium acetate and ammonium formate), andinorganic ammonium such as ammonium carbonate in an acidic solvent suchas lower alkanecarboxylic acid (e.g., formic acid, acetic acid andpropionic acid). In this reaction, when R or R₁ is aromatic heterocycle,isomers may be produced wherein the 4-position R and the 5-position R₁are reversed.

[0090] Compound (I) can be also synthesized by the following route.

[0091] Step 4 wherein X₁ is Hydroxy

[0092] This step, Step 6 and Step 7 are advantageous when R₂ (e.g.,methyl) is converted to other R₂ (e.g., R₂′ such as ethyl).

[0093] When X₁ is hydroxy, compound (VI) can be synthesized by reactingcompound (V) in the presence of a base such as potassium carbonate,lithium hydroxide, sodium hydroxide and potassium hydroxide in anorganic solvent such as methanol, ethanol and dioxane, water or a mixedsolvent thereof from under cooling to under heating.

[0094] Compound (VI) can be also synthesized by the following Step 5.

[0095] Step 5 wherein X₁ is Halogen Atom or Hydroxy

[0096] Compound (VI) can be synthesized by reacting compound (IV) in thepresence of a halogenating agent such as bromine, chlorine andN-bromosuccinimide in an inert solvent such as acetic acid,1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylenechloride, benzene and toluene to give compound (VI) wherein X₁ ishalogen atom. Compound (VI) wherein X₁ is hydroxy can be synthesized byoxidizing compound (IV) with an oxidizing agent such as benzeneiodoacetate, or by treating the halogenated compound (VI) obtained abovewith water in an inert solvent such as acetone, 1,2-dimethoxyethane,dioxane, ether, tetrahydrofuran, benzene and toluene.

[0097] Step 6

[0098] Compound (V′) can be obtained by reacting compound (VI) andcompound (VII′) by a known method. Specifically, compound (VI) whereinX₁ is hydroxy and compound (VII′) wherein X₁′ is halogen atom, orcompound (VI) wherein X₁ is halogen atom and compound (VII′) wherein X₁′is hydroxy are reacted in pyridine, or in the presence of a base such astriethylamine and sodium hydroxide, in an organic solvent such asmethylene chloride, chloroform and ethanol, from under cooling to underheating. When X₁ is halogen atom, alkali metal salt such as sodiumacetate may be used instead of carboxylic acid compound (VII′). In thiscase, a base may or may not be added.

[0099] Step 7

[0100] Compound (I′) can be obtained by treating compound (V′) in thesame manner as in Step 3.

[0101] When a compound wherein either R or R₁ is4-aminosulfonyl-3-fluorophenyl is desired, the compound can be producedfrom a compound having 3-fluoro-4-methylsulfonylphenyl corresponding tothe objective compound by a known method.

[0102] Instead of obtaining compound (IV) using, as mentioned above,compound (II) or (III) having, as R or R₁,

[0103] wherein R₃, R₄, R₅, R₆ and R₇ are as defined above, compound(II′) or (III′) having

[0104] wherein R₄, R₅, R₆ and R₇ are as defined above, may be used as astarting material to give compound (IV′) according to Step 10, whichcompound is then converted to aminosulfonyl or methylsulfonyl accordingto the method of Step 15 to give compound (IV). Alternatively, suchstarting materials (II′) and (III′) may be used to give anon-sulfonylated oxazole compound (XIII) corresponding to the ultimatecompound (I) or (I′) according to Step 1 to Step 7, and the obtainedcompound (XIII) may be subjected to sulfonylation in the same manner asin Step 15 to give the objective compound (I) or (I′).

[0105] When a compound wherein either R or R₁ is phenyl substituted byalkylaminosulfonyl or aminosulfonyl is desired, compound (X) whereineither R₈ or R₉ is methoxysulfonylphenyl is subjected to the followingStep 8 and Step 9 to synthesize compound (IV).

[0106] wherein either R₈ or R₉ is methoxysulfonylphenyl of the formula

[0107] wherein R₄, R₅, R₆ and R₇ are as defined above, and the other isoptionally substituted cycloalkyl, optionally substituted heterocyclicgroup or optionally substituted aryl, and R, R₁, X and X′ are as definedabove.

[0108] Step 8

[0109] Compound (X) can be synthesized in the same manner as in Step 1,using compound (VIII) and compound (IX).

[0110] Step 9

[0111] When at least one of R and R₁ is phenyl having aminosulfonyl oralkylsulfonyl at the 4-position, compound (IV) can be synthesized byheating compound (X) in pyridine, or refluxing compound (X) underheating in the presence of sodium iodide, potassium iodide, lithiumiodide and the like, in an organic solvent such as acetone andtetrahydrofuran, after which the obtained compound is reacted withthionyl chloride or oxalyl chloride under heating. Then, the resultingproduct is aminated or alkylaminated or alkylated by a known method.More specifically, amination or alkylamination is carried out byreacting the resulting product in the presence of aqueous ammonia oralkylamine, or a base such as sodium acetate and ammonium salt such asalkylamine hydrochloride, in an organic solvent such as tetrahydrofuran,ether, toluene, benzene, methylene chloride and dioxane from undercooling to under heating. The alkylation can be carried out by themethod described in J. Org. Chem., 56: 4974-4976 (1991).

[0112] Compound (I) can be also synthesized by the method of thefollowing Step 10 to Step 15.

[0113] This method is directed to finally introducing sulfonyl group inthe last Step 15.

[0114] wherein either R′ or R₁′ is phenyl of the formula

[0115] wherein R₄, R₅, R₆ and R₇ are as defined above, and the other isa group corresponding to one of R and R₁, cycloalkyl which may besubstituted by a substituent such as lower alkyl, heterocyclic groupsuch as thienyl and furyl, which may be substituted by a substituentlower alkyl or halogen atom, or aryl which may be substituted by asubstituent such as halogen atom, lower alkyl and lower alkoxy, and R,R₁, X, X′ and Z are as defined above.

[0116] Step 10

[0117] Compound (IV′) can be synthesized in the same manner as in Step1, wherein compound (II′) and compound (III′) are reacted in thepresence of a metal such as zinc and magnesium in an inert solvent suchas 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylenechloride, benzene and toluene at room temperature. In this case, acatalyst such as palladium(O) complex and copper(I) iodide complex maybe added.

[0118] Step 11

[0119] Compound (XI) can be synthesized by refluxing under heatingcompound (IV′) and hydroxylammine hydrochloride in the presence of abase such as sodium acetate, sodium hydroxide and potassium carbonate inan organic solvent such as methanol, ethanol and tetrahydrofuran, wateror a mixed solvent thereof.

[0120] Step 12

[0121] Compound (XII) can be synthesized by reacting compound (XI) inthe presence of an acylating agent such as acetic anhydride and acetylchloride, in pyridine, or in the presence of a base such astriethylamine in an organic solvent such as methylene chloride andchloroform from under cooling to under heating.

[0122] Step 13

[0123] Compound (XIII) can be synthesized by refluxing under heatingcompound (XII) in an acidic solvent such as formic acid and acetic acid.In this case, a dehydrating agent such as magnesium sulfate and sodiumsulfate may be added.

[0124] Step 14

[0125] This step is for the synthesis of compound (XIII) from compound(XI) in a single step, and compound (XIII) can be synthesized fromcompound (XI) and carboxylic acid chloride such as acetyl chloride bythe method described in Indian J. Chem., 20B: 322-323 (1981). When R₂ ismethyl, compound (XIII) can be synthesized by reacting compound (XI) andacetic anhydride while heating in acetic acid.

[0126] Step 15

[0127] Compound (I) can be synthesized by reacting compound (XIII) inthe presence of a chlorosulfonylating agent such as chlorosulfonic acidin an organic solvent such as chloroform and methylene chloride, orwithout solvent, and subjecting the resulting product to amination,alkylamination or alkylation by a known method. The amination andalkylamination in Step 15 specifically comprise reacting in the presenceof aqueous ammonia, alkylamine or a base such as sodium acetate andammonium salt such as alkylamine hydrochloride in an organic solventsuch as tetrahydrofuran, ether, toluene, benzene, methylene chloride anddioxane from under cooling to under heating. When alkylsulfonation iscarried out, the method described in J. Org. Chem., 56: 4974-4976 (1991)can be used for the synthesis.

[0128] In the above description, alkylsulfonation or aminosulfonation inthe final Step 15 has been exemplarily discussed. It is possible to usecompound (II) and compound (III) instead of the starting materials (II′)and (III′) to give compound (IV), which is followed by Step 11 to Step14 to give an oxazole compound (I). In this case, Step 15 is notnecessary.

[0129] Compound (XIII) used in Step 15 can be also synthesized by thefollowing route.

[0130] wherein R′, R₁′, R₂ and Z are as defined above.

[0131] Step 16

[0132] Compound (V″) can be synthesized in the same manner as in Step 2wherein compound (IV′) is reacted in the presence of lead tetraacetatein acetic acid solvent, or by heating compound (IV′) in the presence ofa complex such as manganese acetate in lower alkanecarboxylic acid suchas acetic acid and propionic acid corresponding to R₂COOH wherein R₂ isas defined above, and benzoic acid and in a solvent such as benzene asnecessary.

[0133] Step 17

[0134] Compound (XIII) can be synthesized in the same manner as in Step3 wherein compound (V″) is refluxed under heating in the presence ofammonium salt such as lower alkanecarboxylic acid ammonium (e.g.,ammonium acetate and ammonium formate) and inorganic ammonium (e.g.,ammonium carbonate) in an acidic solvent of lower alkanecarboxylic acidsuch as formic acid, acetic acid and propionic acid. In this reaction,when R′ or R₁′ is an aromatic heterocycle, isomers may be producedwherein the 4-position R′ and the 5-position R₁′ are reversed.

[0135] Compound (I) can be also synthesized by the method shown in thefollowing Step 18 to Step 21.

[0136] wherein X₂ is halogen atom, and R, R₁, R′, R₁′, R₂ and Z are asdefined above.

[0137] Step 18

[0138] Compound (XV) can be synthesized by reacting compound (XIV) withchlorocarbonate such as ethyl chlorocaronate in an inert solvent such astetrahydrofuran, toluene and ethyl acetate in the presence of a basesuch as triethylamine, or by heating compound (XIV) in acetic anhydride.

[0139] Step 19

[0140] Compound (XVII) can be synthesized by reacting compound (XV) withcompound (XVI) or an acid anhydride corresponding to compound (XVI) inan inert solvent such as tetrahydrofuran, acetonitrile, ethyl acetateand toluene in the presence of magnesium salt such as magnesium chlorideand a base such as triethylamine, pyridine and potassium carbonate.Compound (XVII) can be also synthesized by the method described in Chem.Ber., 102: 883-898 (1969).

[0141] Step 20

[0142] Compound (XVIII) can be synthesized by treating compound (XVII)with an acid such as 1N-4N hydrochloric acid, oxalic solid and dilutesulfuric acid in an inert solvent such as tetrahydrofuran, dioxane,methylene chloride and toluene, or heating compound (XVII) in thepresence of pyridine and acetic acid.

[0143] Step 21

[0144] Compound (I) is obtained by reacting compound (XVIII) with achlorosulfonylating agent such as chlorosulfonic acid in an organicsolvent such as chloroform and methylene chloride, or without solvent.Then, the obtained product is reacted with aqueous ammonia or alkylaminein an organic solvent such as tetrahydrofuran, ether, toluene, methylenechloride and dioxane, or reacted with ammonium salt such as alkylaminehydrochloride in the presence of a base such as sodium acetate, pyridineand sodium hydroxide.

[0145] Compound (I) can be also synthesized from compound (XVIII) by thefollowing Step 22 and Step 23.

[0146] Step 22

[0147] Compound (XIII) can be synthesized by reacting compound (XVIII)with inorganic acid such as concentrated sulfuric acid andpolyphosphoric acid in acetic anhydride, or without solvent, at roomtemperature to under heating.

[0148] Step 23

[0149] Compound (I) can be synthesized by reacting compound (XIII) inthe same manner as in the aforementioned Step 15.

[0150] In the above Step 22 and Step 23, alkylsulfonylation oraminosulfonylation in the final Step 23 has been exemplarily discussed.It is possible to subject a compound having R and R₁ instead of R′ andR₁′ to the reaction according to Step 18 to Step 20, followed by Step 22to give an oxazole compound (I). In this case, Step 23 is not necessary.

[0151] The compound (I) thus obtained can be isolated and purified by aknown method for separation and purification, such as concentration,concentration under reduced pressure, solvent extraction, crystalprecipitation, recrystallization and chromatography.

[0152] The present invention is described in more detail in thefollowing by illustrative Examples and Experimental Examples, to whichthe present invention is not limited.

EXAMPLE 1 Synthesis of5-(2-chloro-4-methylsulfonylphenyl)-4-cyclohexyl-2-methyloxazole(formula (I′); R=cyclohexyl, R₁=2-chloro-4-methyl-sulfonylphenyl,R₂′=methyl, Z=oxygen atom) Step 1) 2-Chloro-4-methylsulfonylbenzylcyclohexyl ketone (formula (IV); R=cyclohexyl,R₁=2-chloro-4-methylsulfonylphenyl)

[0153]

[0154] To a solution of tetrakis(triphenylphosphine)palladium (1.29 g)and zinc powder (2.19 g) in 1,2-dimethoxyethane (10 ml) was added asolution of cyclohexanecarbonyl chloride (3.60 g) in 1,2-dimethoxyethane(10 ml) at room temperature under a nitrogen atmosphere. A solution of2-chloro-4-methylsulfonylbenzyl bromide (9.40 g) in 1,2-dimethoxyethane(20 ml) was gradually added dropwise to the mixture at room temperaturewith stirring. The mixture was further stirred at room temperature for 3hours. The insoluble matter was removed by filtration and the filtratewas concentrated under reduced pressure. Then, ethyl acetate (200 ml)was added to the residue, and the mixture was washed with 1Nhydrochloric acid, and then with saturated aqueous sodiumhydrogencarbonate solution and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated, and ethyl acetate anddiisopropyl ether were added. The precipitated solid was collected byfiltration to give 3.47 g of the title compound as a white solid.

Step 5)2-Bromo-2-(2-chloro-4-methylsulfonylphenyl)-1-cyclohexyl-1-ethanone(formula (VI); R=cyclohexyl, R₁=2-chloro-4-methylsulfonyl-phenyl,X₁=bromine atom)

[0155]

[0156] To a solution of the compound (3.40 g) obtained in the aboveStep 1) in benzene (20 ml) was dropwise added a solution of bromine(1.73 g) in benzene (20 ml) with stirring under ice-cooling, and themixture was stirred for one hour. This solution was poured into waterand extracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium hydrogencarbonate solution and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure to give 4.20 g of the title compound.

Step 6) 1-(2-Chloro-4-methylsulfonylphenyl)-2-cyclohexyl-2-oxoethylacetate (formula (V′); R=cyclohexyl,R₁=2-chloro-4-methylsulfonyl-phenyl, R₂′=methyl, Z=oxygen atom)

[0157]

[0158] Sodium acetate (1.06 g) and ethanol (40 ml) were added to thecompound (4.20 g) obtained in the above Step 5). The mixture wasrefluxed under heating for 4 hours, and the solvent was evaporated underreduced pressure. Ethyl acetate was added to the residue. The mixturewas washed with water and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated to give 3.85 g of a crudeproduct of the title compound.

Step 7)5-(2-Chloro-4-methylsulfonylphenyl)-4-cyclohexyl-2-methyl-oxazole(formula (I′); R=cyclohexyl, R₁=2-chloro-4-methylsulfonyl-phenyl,R₂′=methyl, Z=oxygen atom)

[0159]

[0160] A solution of the compound (3.85 g) obtained in the above Step 6)and ammonium acetate (2.08 g) in acetic acid (40 ml) was refluxed underheating for 5 hours. The solvent was evaporated under reduced pressure,and ethyl acetate was added to the residue. The mixture was washed withwater, saturated aqueous sodium hydrogencarbonate solution and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give 1.95 g of the title compound(yield 53%).

EXAMPLE 2 Synthesis of5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula(I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl,Z=oxygen atom) Step 10) Cyclohexyl 3-fluorobenzyl ketone (formula (IV′);R′=cyclohexyl, R₁′=3-fluorophenyl)

[0161]

[0162] To a solution of tetrakis(triphenylphosphine)palladium (2.00 g)and zinc powder (17.98 g) in 1,2-dimethoxyethane (50 ml) was added asolution of cyclohexanecarbonyl chloride (20.00 g) in1,2-dimethoxyethane (50 ml) at room temperature under a nitrogenatmosphere. A solution of 3-fluorobenzyl bromide (26.00 g) in1,2-dimethoxyethane (100 ml) was gradually added dropwise to the mixturewith stirring under ice-cooling. The mixture was stirred underice-cooling for 30 minutes, and at room temperature for 2 hours. Theinsoluble matter was removed by filtration and the filtrate wasconcentrated under reduced pressure. Then, ethyl acetate (200 ml) wasadded to the residue, and the mixture was washed with 1N hydrochloricacid, and then with saturated aqueous sodium hydrogencarbonate solutionand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give 29.20 g of an oily crude product.

Step 16) 2-Cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate (formula(V″); R′=cyclohexyl, R₁′=3-fluorophenyl, R₂′=methyl, Z=oxygen atom)

[0163]

[0164] Lead tetraacetate (75.00 g) was added to a solution of thecompound (29.20 g) obtained in the above Step 10) in acetic acid (300ml). The mixture was refluxed under heating for 1.5 hours, and thesolvent was evaporated under reduced pressure. Ethyl acetate was addedto the residue. The mixture was washed with water, a saturated aqueoussodium hydrogencarbonate solution and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=9:1) to give18.30 g of the title compound as an oil (yield 50%).

Step 17) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula(XIII); R′=cyclohexyl, R₁′=3-fluorophenyl, R₂=methyl, Z=oxygen atom)

[0165]

[0166] A solution of the compound (18.00 g) obtained in the above Step16) and ammonium acetate (15.00 g) in acetic acid (100 ml) was refluxedunder heating for 5 hours, and the solvent was evaporated under reducedpressure. Ethyl acetate was added to the residue. The mixture was washedwith water, saturated aqueous sodium hydrogencarbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give 17.20 g of an oily crudeproduct.

Step 15)5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexy1-2-methyl-oxazole(formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl,R₂=methyl, Z=oxygen atom)

[0167]

[0168] To a solution of the compound (17.00 g) obtained in the aboveStep 17) in chloroform (80 ml) was added dropwise chlorosulfonic acid(27 ml) with stirring under ice-cooling, and the mixture was heated at100° C. for 3 hours. The reaction mixture was cooled to roomtemperature, and dropwise added tc ice-water (300 ml) with stirring. Theorganic layer was separated, washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give 20.31 g of a crude product.

[0169] Aqueous ammonia (28%) was added to a solution of the obtainedcompound (10.00 g) in tetrahydrofuran (40 ml) with stirring at roomtemperature, and the mixture was stirred at room temperature for onehour. The solvent was evaporated under reduced pressure and ethylacetate was added to the residue. The mixture was washed with water andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated, and the residue was separated and purified by silica gelcolumn chromatography (developing solvent; dichloromethane:ethylacetate=6:1) to give 5.74 g of the title compound (yield 61%).

EXAMPLE 2′

[0170] The compound of Example 2 (formula (I); R=cyclohexyl,R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom) wassynthesized according to another synthetic method.

Step 11) Cyclohexyl 3-fluorobenzyl ketone oxime (formula (XI);R′=cyclohexyl, R₁′=3-fluorophenyl)

[0171]

[0172] To a solution of the compound (353 g) obtained according to amethod similar to that of the above Example 2, Step 10) in ethanol (1300ml) were added hydroxylamine hydrochloride (123 g) and sodium acetate(158 g). The mixture was refluxed under heating for 2 hours, and thesolvent was evaporated under reduced pressure. Ethyl acetate was addedto the residue. The mixture was washed with water, saturated aqueoussodium hydrogencarbonate solution and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the crude product was recrystallized from n-heptane togive 160 g of the title compound (yield 42%).

Step 14) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula(XIII); R′=cyclohexyl, R₁′=3-fluorophenyl, R₂=methyl, Z=oxygen atom)

[0173]

[0174] Acetic anhydride (95 ml) was dropwise added to a solution of thecompound (158 g) obtained in the above Step 11) in acetic acid (900 ml)with stirring at room temperature, and the mixture was refluxed underheating for 7 hours. The solvent was evaporated under reduced pressureand n-heptane was added to the residue. The mixture was washed withwater, saturated aqueous sodium hydrogencarbonate solution, saturatedbrine and acetonitrile. The solvent was evaporated under reducedpressure to give 119 g of the title compound as an oil.

[0175] Then, the obtained compound (119 g) was reacted in the samemanner as in the above Example 2, Step 15) to give a compound of Example2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl,R₂=methyl, Z=oxygen atom).

EXAMPLE 3 Synthesis of4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole(formula (I); R=cyclohexyl, R₁=3-fluoro-4-methyl-sulfonylphenyl,R₂=methyl, Z=oxygen atom) Step 15)4-Cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyl-oxazole(formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonyl-phenyl,R₂=methyl, Z-oxygen atom)

[0176]

[0177] To a solution of the compound (17.00 g) obtained in the aboveExample 2, Step 17) in chloroform (80 ml) was dropwise addedchlorosulfonic acid (27 ml) with stirring under ice-cooling. The mixturewas heated at 100° C. for 3 hours. The reaction mixture was cooled toroom temperature and dropwise added to ice-water (300 ml) with stirring.The organic layer was separated, washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give 20.31 g of a crude product.

[0178] Water (25 ml) was added to the obtained compound (3.66 g). To themixture were added sodium sulfite (1.42 g) and sodium hydrogencarbonate(1.89 g) successively with stirring at room temperature. The mixture washeated at 70° C. for 2 hours. Ethanol (25 ml) and methyl iodide (2.20 g)were added to the mixture, and the mixture was heated at 100° C. for 2hours. The mixture was cooled to room temperature and extracted withethyl acetate. The extract was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was saparated and purified by silica gelcolumn chromatography (developing solvent; hexane:ethyl acetate=2:1) togive 0.82 g of the title compound (yield 24%).

EXAMPLE 4-6

[0179] The compounds of Examples 4-6 were obtained in the same manner asin Examples 1-3 or Example 7 to be mentioned below.

[0180] The structures and properties of the compounds of Examples 1-6are shown in the following Tables. In the Tables, Me means methyl. TABLE1 Ex. Compound m.p. ¹H NMR (δ) ppm IR cm⁻¹ MS Elem. analysis 1

119˜121° C. white crystals CDCl₃ 300 MHz 1.1-1.2 (3H, m) 1.6-1.8 (7H, m)2.48 (1H, m) 2.51 (3H, s) 3.12 (3H, s) 7.55 (1H, d, J = 8.1 Hz) 7.88(1H, dd, J = 1.8, 8.1 Hz) 8.07 (1H, # d, J = 1.8 Hz) neat 2928 1578 13171155 1100  960 FAB+354 (MH⁺) 2

166˜167° C. white crystals CDCl₃ 300 MHz 1.3-1.5 (3H, m) 1.6-1.9 (7H, m)2.51 (3H, s) 2.79 (1H, tt, J = 3.7, 11.3 Hz) 5.11 (2H,s) 7.36-7.44 (2H,m) 7.94 (1H, # t, J = 7.9 Hz) neat 3280 2929 1613 1343 1170 FAB+339(MH⁺) Calculated C 56.79% H 5.66% N 8.28% Found C 56.41% H 5.73% N 8.19%3

111˜112° C. white crystals CDCl3 300 MHz 1.3-1.5 (3H, m) 1.6-1.8 (7H, m)2.52 (3H, s) 2.80 (1H, tt, J = 4.0, 11.4 Hz) 3.25 (3H, s) 7.40 (1H, dd,J = 1.6, 11.2 Hz) 7.48 (1H, dd, J = 1.6, 8.3 Hz) # 7.99 (1H, dd, J =8.3,8.4 Hz) neat 2929 1612 1320 1161 1144  769 FAB+338 (MH⁺) Calculated C60.52% H 5.97% N 4.15% Found C 60.70% H 6.10% N 4.12%

[0181] TABLE 2 Ex. Compound m.p. ¹H NMR (δ) ppm IR cm⁻¹ MS Elem.analysis 4

200˜201° C. white crystals CDCl₃ 300 MHz 1.28-1.44 (4H, m) 1.62-1.92(6H, m) 2.51 (3H,s) 2.72-2.83 (1H, m) 5.18 (2H, s) 7.53 (1H, dd, J =8.4, 1.6 Hz) 7.69 (1H, d, J = 1.6 Hz) 8.13 (1H, d, J = 8.4 Hz) # KBr3353 3255 2928 1606 1342 1166 FAB+355 (MH⁺) Calculated C 54.16% H 5.40%N 7.89% Found C 54.11% H 5.45% N 7.78% 5

183.2˜184.2° C. white crystals CDCl₃ 300 MHz 1.3-1.5 (3H, m) 1.7-1.9(7H, m) 2.50 (3H, s) 2.73 (3H, s) 2.80 (1H, m) 4.92 (2H, s) 7.43-7.49(2H,m) 8.05 (1H, d, J = 8.3 Hz) # KBr 3294 2929 1609 1299 1170 FAB+335(MH⁺) Calculated C 61.05% H 6.63% N 8.38% Found C 61.24% H 6.73% N 8.43%6

amorphous CDCl₃ 300 MHz 1.28-1.47 (3H, m) 1.57-1.95 (7H, m) 2.51 (3H, s)2.68-2.80 (1H, m) 5.37 (2H, brs) 7.18 (2H, ddd, J = 9.9, 1.7, 1.4 Hz)KBr 2931 1622 1557 1422 1359 1175 1035 FAB+357 (MH⁺)

EXAMPLE 7 Synthesis of5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole(formula (I); R=4-fluorophenyl, R₁=4-aminosulfonyl-3-fluorophenyl,R₂=methyl, Z=oxygen atom)

[0182]

[0183] A solution of5-(3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole (1.10 g) obtainedby the method as mentioned above and chlorosulfonic acid (1.6 ml) inchloroform (2 ml) was heated with stirring at 90° C. for 2 hours. Thereaction mixture was poured into ice-water and extracted withchloroform. The organic layer was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated to give 1.06 gof a crude product of5-(4-chlorosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole.

[0184] To a solution of this crude product (1.06 g) in tetrahydrofuran(6 ml) was added 28% aqueous ammonia (0.6 ml) and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated, added with ethyl acetate, and washed with water andsaturated brine. The ethyl acetate solution was dried over anhydrousmagnesium sulfate, and concentrated to give 981 mg of a crude product.This crude product was recrystallized from ethanol to give 629 mg of thetitle compound (yield 44%). The structure and properties of thiscompound are shown in the following Table. TABLE 3 Ex. Compound m.p. ¹HNMR (δ) ppm IR cm⁻¹ MS Elem. analysis 7

208° C. white crystals CDCl₃ 300 MHz 2.58 (3H, s) 5.07 (2H, s) 7.14 (2H,tt, J = 2.2, 8.8 Hz) 7.36 (1H, dd, J = 1.5, 11.0 Hz) 7.47 (1H, dd, J =1.8, 7.7 Hz) 7.59 (2H, ddd, J = 2.2, 5.5, 8.8 Hz) 7.88 (1H, t, J = 7.7Hz) # neat 3278 2359 1613 1562 1510 1342 1171 FAB+351 (M⁺ + 1)Calculated C 54.74% H 3.85% N 7.66% Found C 54.40% H 3.74% N 7.59%

EXAMPLE 2″

[0185] The compound of Example 2 (formula (I); R=cyclohexyl,R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom) wassynthesized according to another synthetic method.

Step 18) 4-Cyclohexyl-2-methyl-5-oxazolone (formula (XV); R′=cyclohexyl,R₂=methyl)

[0186]

[0187] Triethylamine (8.39 ml) was added to a suspension ofDL-N-acetyl-2-cyclohexylglycine (10.00 g) obtained fromα-aminophenylacetic acid according to a known method [Collect. Czeck.Chem. Commun., 31: 4563 (1996)] in ethyl acetate (50 ml). Ethylchlorocarbonate (5.28 ml) was dropwise added to the mixture underice-cooling. The mixture was stirred under ice-cooling for one hour,added with ethyl acetate (150 ml), and washed successively with waterand saturated brine. The ethyl acetate solution was concentrated underreduced pressure to give 9.86 g of the title compound as an oil.

Step 19) 4-Cyclohexyl-4-(3-fluorobenzoyl)-2-methyl-5-oxazolone (formula(XVII); R′=cyclohexyl, R₁′=3-fluorophenyl, R₂=methyl, Z=oxygen atom)

[0188]

[0189] A solution of the compound (9.86 g) obtained in the above Step18) in tetrahydrofuran (15 ml) was added to a suspension of magnesiumchloride (3.56 g) in tetrahydrofuran (20 ml). Triethylamine (9.49 ml)was added with stirring under ice-cooling, and the mixture was stirredfor 15 minutes. 3-Fluorobenzoyl chloride (4.55 ml) was dropwise added tothe mixture, and the mixture was stirred under ice-cooling for one hour.The reaction mixture was diluted with ethyl acetate, washed with water,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure to give 11.69 g of the title compound as an oil.

Step 20) 2-N-Acetylamino-2-cyclohexyl-3′-fluoroacetophenone (formula(XVIII); R′=cyclohexyl, R₁′=3-fluorophenyl, R₂=methyl, Z=oxygen atom)

[0190]

[0191] To a solution of the compound (527 mg) obtained in the above Step19) in tetrahydrofuran (3.5 ml) was added 1N hydrochloric acid (0.35ml). The mixture was stirred at room temperature for one hour, addedwith ethyl acetate, and washed successively with water, saturatedaqueous sodium hydrogencarbonate solution and saturated brine. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure to give 404 mg of the titlecompound as a solid (yield 84%). The solid was recrystallized fromn-heptane to give white crystals, melting point 116-117° C.

Step 21) 5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole(formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl,R₂=methyl, Z=oxygen atom)

[0192]

[0193] Chlorosulfonic acid (0.34 ml) was added to a solution of thecompound (200 mg) obtained in the above Step 20) in chloroform (2 ml)with stirring under ice-cooling, and the mixture was refluxed underheating for 5 hours. The reaction mixture was diluted with chloroformand poured into ice-water. The organic layer was separated, washedsuccessively with water and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive 181 mg of a crude product.

[0194] To a solution of the obtained compound (169 mg) intetrahydrofuran (2 ml) was added 28% aqueous ammonia (0.1 ml) withstirring at room temperature, and the mixture was stirred for 30minutes. The solvent was evaporated under reduced pressure. Ethylacetate was added to the residue, and the mixture was washedsuccessively with water and saturated brine, which was followed bydrying over anhydrous sodium sulfate. The solvent was evaporated, andthe residue was separated and purified by silica gel columnchromatography (developing solvent; dichloromethane:ethyl acetate=6:1)to give 126 mg of the title compound (yield 55%).

EXAMPLE 2′″

[0195] The compound of Example 2 (formula (I); R=cyclohexyl,R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom) wassynthesized according to another synthetic method.

Step 22) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula(XIII); R′=cyclohexyl, R₁′=3-fluorophenyl, R₂=methyl)

[0196]

[0197] Concentrated sulfuric acid (30 μl ) was added to a suspension ofthe compound (141 mg) obtained in the above Example, Step 20) in aceticanhydride (2 ml), and the mixture was stirred at 100° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, added withaqueous potassium carbonate solution, and extracted with ethyl acetate.The organic layer was washed with water and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give 135mg of the title compound as an oil.

Step 23) 5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole(formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl,R₂=methyl, Z=oxygen atom)

[0198]

[0199] In the same manner as in the above Example 2, Step 15), thecompound obtained in the above Step 22) was reacted to give the compoundof Example 2 (formula (I); R=cyclohexyl,R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom).

Experimental Example 1

[0200] (Inhibitory Action on Cyclooxygenase)

[0201] The enzymatic activity was determined from the percent conversionof ¹⁴C arachidonic acid into prostaglandin H₂ (PGH₂) and the decomposedproduct thereof. That is, a test sample (20 μl), an enzyme solution (20μl) and distilled water (10 μl) were added to 100 mM Tris-HCl buffer (pH8, 140 μl) containing hematin (2 μM) and tryptophan (5 mM), and themixture was thoroughly stirred, which was followed by preincubation at24° C. for 5 minutes. Then, a ¹⁴C arachidonic acid solution (10 μl) wasadded and the mixture was reacted at 24° C., whereafter a solution (40μl) of ethyl ether/methanol/1M citric acid (30/4/1) ice-cooled to −20°C. was added to stop the reaction. The reaction mixture was centrifugedfor 5 minutes at 3,000 rpm to give an ether layer which was placed on athin plate, and developed with ethyl ether/methanol/acetic acid(90/2/0.1) to determine percent conversion (A) from arachidonic acid toPGH₂ and the decomposed product thereof. The percent conversion (B)without a test sample was also determined, based on which percentinhibition was calculated from the following formula, and aconcentration (IC₅₀) necessary for 50% inhibition of the test sample wasdetermined.

Inhibition (%)=(1−A/B)×100

[0202] An enzyme prepared from human platelets was used as an enzymesolution of cyclooxygenase-1, and an enzyme expressed by a yeast, intowhich cDNA of human cyclooxygenase-2 had been introduced using a kit ofInvitrogen Corp., was used as an enzyme solution of cyclooxygenase-2. Asused herein, control compound 1 was5-(4-aminosulfonylphenyl)-4-cyclohexyl-2-methyloxazole, a patentapplication to which has been previously filed by us, and controlcompound 2 was a known analogous compound,5-(4-aminosulfonylphenyl)-4-(4-fluorophenyl)-2-methyloxazole.

[0203] The results are shown in Table 4.

[0204] As is evident from the comparison of control compound 1 and thecompound of Example 2, as well as control compound 2 and the compound ofExample 7, a remarkable reduction of the action on COX-1 while retainingthe activity on COX-2 has become possible particularly by introducingfluorine atom. TABLE 4 Experimental Example 1 (inhibitory action oncyclooxygenase) Structural IC₅₀ (μM) Example formula COX-2 COX-1COX-1/COX-2 2

0.07 >100 >1,428 3

0.3 >100 >333 4

>10 5

>10 6

0.16 >100 >625 7

0.03 37 1,233 Indomethacin 8 0.5 0.063 Control 1

0.07 45 643 Control 2

0.02 5 250

Experimental Example 2

[0205] (Effects on Carrageenin-induced Podedema)

[0206] Carrageenin (1%, 0.05 ml) dissolved in physiological saline wassubcutaneously injected to the left hindlimb of male Donryu rats toinduce podedema. The degree of podedema was evaluated by measuring thevolume of the limb 3 hours after carrageenin administration. A testcompound (1, 3, 10 or 30 mg/kg) was orally administered one hour beforecarrageenin administration, and suppression thereby was studied.Inhibitory activity was expressed by the dose (ED₃₀) of the testcompound necessary for inhibiting by 30% relative to the control group.The results are shown in Table 5. TABLE 5 Experimental Example 2(effects on carrageen-induced podedema in rats) carrageen in-inducedpodedema Example in rats, ED₃₀ (mg/kg p.o.) 2 5.5 indomethacin 2.9

Industrial Applicability

[0207] The compound of the present invention, in particular, a compoundwherein R₃ is methyl or amino, R₅ is fluorine atom, R₆ is hydrogen atomor fluorine atom, and R₄ and R₇ are hydrogen atom, and pharmaceuticallyacceptable salts thereof surprisingly selectively inhibit COX-2 alone,while scarcely inhibiting COX-1. Accordingly, the compound of thepresent invention possesses superior antipyretic action, analgesicaction and anti-inflammatory action that the conventional productscannot afford, and scarcely show side-effects in the digestive tract.

[0208] Consequently, the development of a superior anti-inflammatoryagent heretofor not existed has been enabled, which in turn producesgreat expectation of the provision of a practical therapeutic agent forthe diseases possibly caused by COX-2 product, such as asthma andrheumatism.

What is claimed is:
 1. A heterocyclic aromatic oxazole compound of theformula (I)

wherein Z is an oxygen atom; one of R and R₁ is a group of the formula

wherein R₃ is lower alkyl, amino or lower alkylamino, and R₄, R₅, R₆ andR₇ are the same or different and each is hydrogen atom, halogen atom,lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, providedthat at least one of R₄, R₅, R₆ and R₇ is not hydrogen atom, and theother is optionally substituted cycloalkyl, optionally substitutedheterocyclic group or optionally substituted aryl; and R₂ is a loweralkyl or a halogenated lower alkyl, or a pharmaceutically acceptablesalt thereof.
 2. The heterocyclic aromatic oxazole compound of claim 1,wherein R₁ is a group of the formula

wherein R₃′ is lower alkyl or amino, at least one of R₄′, R₅′, R₆′ andR₇′ is halogen atom or lower alkyl and the rest is hydrogen atom orhalogen atom, or a pharmaceutically acceptable salt thereof.
 3. Theheterocyclic aromatic oxazole compound of claim 1, wherein R₁ is a groupof the formula

wherein R₃″ is methyl or amino, R₅″ is fluorine atom and R₆″ is hydrogenatom or fluorine atom, and R₂ is methyl, or a pharmaceuticallyacceptable salt thereof.
 4. The heterocyclic aromatic oxazole compoundof claim 1, wherein R₁ is a group of the formula

wherein R₃″, R₅″ and R₆″ are as defined in claim 3; R is optionallysubstituted cycloalkyl having 5 to 7 carbon atoms, optionallysubstituted thienyl, optionally substituted furyl, optionallysubstituted pyrrolyl, optionally substituted morpholino, optionallysubstituted piperazinyl, optionally substituted piperidyl, optionallysubstituted phenyl, optionally substituted naphthyl or optionallysubstituted biphenyl, and R₂ is methyl, or a pharmaceutically acceptablesalt thereof.
 5. The heterocyclic aromatic oxazole compound of claim 4,wherein R₃″ is amino, or a pharmaceutically acceptable salt thereof. 6.The heterocyclic aromatic oxazole compound of claim 4, wherein R isoptionally substituted cycloalkyl having 5 to 7 carbon atoms, optionallysubstituted phenyl or optionally substituted thienyl, or apharmaceutically acceptable salt thereof.
 7. The heterocyclic aromaticoxazole compound of claim 4, wherein R is cyclohexyl or 4-fluorophenyl,and R₁ is 4-aminosulfonyl-3-fluorophenyl,4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or3,5-difluoro-4-methylsulfonylphenyl, or a pharmaceutically acceptablesalt thereof.
 8. The heterocyclic aromatic oxazole compound of claim 1,which is selected from the group consisting of:4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole,5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole,4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazole,and5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole,or a pharmaceutically acceptable salt thereof.
 9. An oxime compound ofthe following formula (XI′)

wherein R₁″ is

wherein R₄, R₅, R₆ and R₇ are as defined in claim 1, and R″ isoptionally substituted cycloalkyl or optionally substituted aryl. 10.The oxime compound of claim 9 wherein R₁″ is 3-fluorophenyl or3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.
 11. A ketonecompound of the following formula (IV″)

wherein R₁″ and R″ are respectively as defined in claim
 9. 12. Theketone compound of claim 11, wherein R₁″ is 3-fluorophenyl or3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.
 13. Aketomethylene compound of the following formula (IV′″)

wherein R′″ is an optionally substituted cycloalkyl having 5 to 7 carbonatoms, an optionally substituted phenyl or an optionally substitutedthienyl, and R₁′″ is a group of the formula

wherein R₃′, R₄′, R₅′, R₆′ and R₇′ are as defined in claim
 2. 14. Theketomethylene compound of claim 13, wherein R′″ is cyclohexyl, and R₁′″is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl,3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl.15. An ester compound of the following formula (V)

wherein R, R₁, R₂ and Z are as defined in claim
 1. 16. The estercompound of claim 15, wherein R is cycloalkyl and R₂ is lower alkyl. 17.An amide compound of the following formula (XVIII′)

wherein R₁″ and R″ are respectively as defined in claim 9, and Z and R₂are as defined in claim
 1. 18. The amide compound of claim 17, whereinR₁″ is 3-fluorophenyl or 3,5-difluorophenyl, R″ is cyclohexyl or4-fluorophenyl, and R₂ is lower alkyl.
 19. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, and a heterocyclicaromatic oxazole compound of claim 1 or a pharmaceutically acceptablesalt thereof.
 20. A cyclooxygenase-2 inhibitor comprising apharmaceutically acceptable carrier, and a heterocyclic aromatic oxazolecompound of claim 1 or a pharmaceutically acceptable salt thereof as anactive ingredient.
 21. An anti-inflammatory agent comprising apharmaceutically acceptable carrier, and a heterocyclic aromatic oxazolecompound of claim 1 or a pharmaceutically acceptable salt thereof as anactive ingredient.